Population Genetics of Mobile Elements

描述(申请人提供)：散布的重复元素，包括Alu和LINE1(Li)元素，占人类基因组的45%，但对它们的起源和动态仍有许多未知之处。有证据表明，这些元素会影响基因多样性在整个基因组中的分布，因为它们会影响重组等过程。该项目的目标是在前一个资助期所获得的知识的基础上，探讨Alu和Li元素的起源及其对基因组多样性模式的影响。通过一系列的聚合酶链式反应和测序实验，我们将评估基因转化对Alu多样性的影响。我们将评估50个基因组区域的连锁不平衡模式，以检验Alu元素介导同源重组的假设。我们将对人类和黑猩猩的基因组进行比较，以检验Alu元件是不平等交换事件、删除和复制基因的重要中介这一假设。我们预测，由于Li元素在基因组中的分布和密度较低，它们作为不等交换的媒介的频率较低。我们设计了一系列实验来检验这一假设，即Alu元素以不依赖于核酸内切酶的方式插入基因组，因此可能参与双链DNA断裂的修复。最后，我们将应用新开发的方法来确定自然选择是否对人类基因组中的Alu和Li元素起作用。 基因转换和重组等因素对基因组多样性模式产生重要影响，而基因组多样性模式又影响基因组中的连锁不平衡模式。这项研究将有助于探索重复元件对基因组多样性的影响，因此将对利用连锁不平衡来定位致病基因具有重要意义。通过更好地理解这些元件在DNA修复和基因复制和缺失中的作用，我们对遗传病的理解也将得到加强。

DESCRIPTION (provided by applicant): Interspersed repetitive elements, including Alu and LINE1 (LI) elements, make up 45% of the human genome, yet much remains unknown about their origins and dynamics. There is evidence that these elements affect the distribution of genetic diversity across the genome because of their influence on processes like recombination. The goals of this project are to build upon the knowledge gained from the previous funding period in order to pursue questions about the origins of Alu and LI elements and about their effects on patterns of genomic diversity. Using a series of PCR and sequencing experiments, we will evaluate the effects of gene conversion on Alu diversity. We will assess linkage disequilibrium patterns in 50 genomic regions to test the hypothesis that Alu elements mediate homologous recombination. We will undertake comparisons of human and chimpanzee genomes to test the hypothesis that Alu elements are important mediators of unequal crossover events, deleting and duplicating genes. We predict that LI elements, because of their observed distribution and their lower density in the genome, function less frequently as mediators of unequal crossover. We have designed a series of experiments to test the hypothesis that Alu elements insert into the genome in an endonuclease-independent fashion and may therefore participate in the repair of double-stranded DNA breaks. Finally, we will apply newly developed methods to determine whether natural selection has been operating on Alu and LI elements in the human genome. Factors like gene conversion and recombination exert important effects on patterns of genomic diversity, which in turn influence patterns of linkage disequilibrium in the genome. The proposed research, which will help to explore the influence of repetitive elements on genomic diversity, will thus have important implications for the use of linkage disequilibrium in localizing disease-causing genes. Our understanding of genetic disease will also be enhanced by a better understanding of the role of these elements in DNA repair and in gene duplication and deletion.